The ultimate goal of this Fast Track Phase I/II SBIR proposal is to develop the novel pharmaceutical agent 131I-MIP-1145, as a molecular targeting radio-therapeutic treatment for metastatic melanoma. Preliminary results with the former lead compound were highly successful in animal tumor models and human melanoma patients. During purity testing for animal safety studies, radiolysis induced degradation at high radioactive concentrations prohibited development of the first generation compound. Chemical and preclinical evaluation identified the compound MIP-1145 to have greater chemical stability with more desirable distribution properties in animals. 131I-MIP-1145 is a radio-iodinated benzamide molecule with extremely high selective binding to melanin expressing melanomas with prolonged retention and low non-target organ accumulation. The molecular target specificity and high tumor accumulation of 131I-MIP-1145 are ideal properties for an agent to effectively treat melanoma metastasis. Preliminary preclinical efficacy studies demonstrated complete tumor remission after two treatments with 131I-MIP-1145 in a SK-Mel-3 human melanoma xenograft mouse model. The first six month phase of this proposal will focus on developing a stable formulation for large doses (150 mCi) of high specific activity 131I-MIP-1145. The formulation composition must be firmly established prior to conducting extensive pre-clinical safety and efficacy studies. The second phase of the proposal will focus on developing a continuous flow production process that will be validated on an automated laboratory synthesis system, to reduce radiation exposure to personnel and provide sufficient levels of activity for therapeutic clinical trials. To produce material for human testing, a GMP production campaign for the critical component precursor and reference standard must be initiated. Radioactive 131I-MIP-1145 material from pre-validation productions will also be used to perform animal safety and toxicity testing. The data on process development chemistry, manufacturing and controls, analytical testing, chemical stability as well as pre-clinical toxicity studies will be the backbone of an application to the FDA. The justification for requesting Fast Track consideration is to have the therapeutic scale production batch ready to treat patients as soon as the imaging / dosimetry study is performed in human melanoma patients. The innovation in this proposal is the exciting promise for a potential curative therapeutic treatment of metastatic melanoma. Following successful completion of the SBIR program, Molecular Insight will develop a clinical protocol for an industry sponsored IND application to the FDA. [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Systemic radiotherapy for metastatic melanomas: Innovation of a novel radiopharmaceutical agent exclusively targeting melanin in malignant melanocytes. The incidence of malignant melanoma is rising faster than that of any other types of cancer in the United States. A radiopharmaceutical, capable of being labeled with cell destroying radioisotopes and exclusively targeted to melanoma tissue, would provide a drug specific for the treatment of metastatic disease. The successful development of an I-131 labeled molecular targeting radiotherapeutic agent for malignant melanoma would introduce this therapeutic technique to a now incurable disease and bring considerable attention to the field of therapeutic radiology. Molecular Insights potential new drug: 131I-MIP-1145 would enable systemic radiotherapy target to melanin positive metastatic melanomas combined with personalized dose administration and therapeutic follow-up. The rising incidence of malignant melanomas, the early and wide-spread occurrence of metastases, and the poor response rates for current therapies, represents a life saving and valuable commercial opportunity for an effective treatment for patients with metastatic melanomas. [unreadable] [unreadable] [unreadable]